The purpose of this Phase II project is to develop a new treatment for pulmonary arterial hypertension (PAH) consisting of the inhaled platelet derived growth factor receptor (PDGFR) inhibitor PK10453. PAH is a disease of the pulmonary vasculature associated with high morbidity and mortality. Signaling through the PDGFR leads to smooth muscle cell proliferation which contributes to the development of PAH. The prior phase I study met the key quantitative milestone of demonstrating efficacy of inhaled PK10453 in two animal models of PAH. The Specific Aims of this phase II proposal consist of the following: 1) formulate PK10453 for a metered-dose inhaler (MDI) or as a dry powder for inhalation delivery; 2) Perform pharmacokinetic, pharmacodynamic, and maximum tolerated dose studies of the inhaled formulation. Aim one will define the physical and chemical characteristics of PK10453 in order to identify the most thermodynamically stable form of the compound. Based on this initial characterization, which will include a study of the salt forms of the compound, a formulation as a suspension or solution in an MDI may be developed. Alternatively PK10453 will be micronized then blended with a lactose carrier for a dry powder inhaler (DPI). Other strategies to develop a stable, reproducible inhaled formulation of PK10453 include spray drying techniques. Aim 2 will perform pharmacokinetic studies of inhaled compound, determine maximum tolerated dose in the rat and determine the formulation that decreases pulmonary hypertension without causing adverse effects on lung function or systemic blood pressure in the rat monocrotaline plus pneumonectomy model. At the conclusion of this project, the inhaled formulation of PK10453 will have been identified for pivotal IND enabling studies. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension is a devastating disease with a high morbidity and mortality. This project is relevant to public health because it will ultimatel lead to a new treatment for pulmonary arterial hypertension.